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The incidence of enteric infections in broiler chickens may increase worldwide due to mounting pressure to limit the use of sub-therapeutic antibiotics and ionophores for coccidia suppression/prevention in the diets of broilers. For this reason, we need expand our knowledge on the role that micro-minerals have in modulating the intestinal physiology, immunology, and microbiology of broiler chickens. There are issues associated with the use of high doses of some micro-minerals in the diets of animals, such as environmental contamination, bacterial resistance, and gizzard erosion. Therefore, there is a need to maximize the absorption of these minerals by the gastrointestinal tract (GIT) of birds when intestinal function may be compromised. Zinc is an essential micromineral required for growth, and influences intestinal development and/or regeneration during and after enteric disease. Two studies were conducted by our lab to determine the effects of Zn source in broilers under coccidia and challenge. In the first study, Zn proteinate had beneficial effects on the performance of chickens challenged with coccidia plus by enhancing intestinal integrity and partially attenuating the inflammatory response. In the second study, Zn proteinate lowered the expression of pro-inflammatory cytokines and modulated the ileal microbiota. Additionally, the poultry industry has used prophylactic concentrations of dietary Cu for its ability to improve feed conversion for a long time. Copper absorption occurs mainly in the duodenum of chickens and, therefore, injuries to the intestinal epithelium of duodenum would impair Cu absorption and decrease its tissue concentration. Although there is a lack of studies relating Mn supplementation and its different sources on the immune response against coccidiosis in poultry, it is likely that Mn is beneficial during enteric challenges due to its role in the production of mucopolysaccharides. Therefore, the proper evaluation of the role of minerals on mitigating the negative impact of coccidiosis in broilers must consider their properties in modulating the physiology, immunology, and the intestinal microbiota of the host during health and disease situation events.

For poultry producers, chronic low-grade intestinal inflammation has a negative impact on productivity by impairing nutrient absorption and allocation of nutrients for growth. Understanding the triggers of chronic intestinal inflammation and developing a non-invasive measurement is crucial to managing gut health in poultry. In this study, we developed two novel models of low-grade chronic intestinal inflammation in broiler chickens: a chemical model using dextran sodium sulfate (DSS) and a dietary model using a high non-starch polysaccharide diet (NSP). Further, we evaluated the potential of several proteins as biomarkers of gut inflammation. For these experiments, the chemical induction of inflammation consisted of two 5-day cycles of oral gavage of either 0.25mg DSS/ml or 0.35mg DSS/ml; whereas the NSP diet (30% rice bran) was fed throughout the experiment. At four times (14, 22, 28 and 36-d post-hatch), necropsies were performed to collect intestinal samples for histology, and feces and serum for biomarkers quantification. Neither DSS nor NSP treatments affected feed intake or livability. NSP-fed birds exhibited intestinal inflammation through 14-d, which stabilized by 36-d. On the other hand, the cyclic DSS-treatment produced inflammation throughout the entire experimental period. Histological examination of the intestine revealed that the inflammation induced by both models exhibited similar spatial and temporal patterns with the duodenum and jejunum affected early (at 14-d) whereas the ileum was compromised by 28-d. Calprotectin (CALP) was the only serum protein found to be increased due to inflammation. However, fecal CALP and Lipocalin-2 (LCN-2) concentrations were significantly greater in the induced inflammation groups at 28-d. This experiment demonstrated for the first time, two in vivo models of chronic gut inflammation in chickens, a DSS and a nutritional NSP protocols. Based on these models we observed that intestinal inflammation begins in the upper segments of small intestine and moved to the lower region over time. In the searching for a fecal biomarker for intestinal inflammation, LCN-2 showed promising results. More importantly, calprotectin has a great potential as a novel biomarker for poultry measured both in serum and feces.

The objective of this study was to determine the effects of two levels of a precision biotic (PB) within a reduced CP diet for performance, digestibility, and blood biomarkers in Dekalb White laying hens from 24 to 42 weeks of age. A total of four diets were fed: (1) an industry-standard positive control (PC) diet with a formulated CP level of 17.5%; (2) a negative control (NC) diet with a formulated CP level of 15.5%; (3) NC with 0.5 kg/ton PB (NC+PB1); (4) NC with 0.7 kg/ton PB (NC+PB2). The NC diet decreased hen–day egg production compared to the PC diet, and supplementation with both levels of PB led to intermediate levels of production. There was a similar trend for the feed conversion ratio (FCR), measured in kilograms of feed per dozen eggs. Feed cost was lower in the reduced CP diets compared to the PC. Apparent total tract digestibility was decreased with PB supplementation without differences in apparent ileal digestibility. The increased plasma uric acid levels in the NC+PB2 group suggest a shift in protein metabolism toward higher efficiency in ammonia detoxification. While more research is needed on PB, this research suggests that supplementation with PB in laying hens could potentially improve performance parameters.

A dietary glycan-based precision biotic (Glycan PB) was evaluated on the performance, welfare indicators, and litter characteristics of broiler chickens. In Trial 1, the main effects of Glycan PB dose (0, 250 and 500 g/metric ton (MT)) and xylanase supplementation (0 or 100 g/MT) were tested, as was their interaction. In Trial 2, pens located inside a commercial house were used to test the effect of Glycan PB supplementation (500 g/MT) versus a control diet. In Trial 1, Glycan PB supplementation at 250 and 500 g/MT improved feed conversion ratio (FCR) by 7 and 11 points when compared to diets without Glycan PB (p < 0.001). At 35 d, Glycan PB reduced the pH and ammonia concentration in diets with xylanase. In Trial 1, the supplementation with 500 g of Glycan PB/MT of feed reduced litter scores (p < 0.05). In both trials, 500 g of Glycan PB/MT of feed increased the proportions of birds without footpad lesions (Trial 1: 72.2% vs. 82.7%; p < 0.001; Trial 2: 14 to 27.3% (p = 0.05) or gait defects (Trial 1: 96.1% vs. 98.4%; p < 0.001) and decreased the proportion of birds with footpad lesions (Trial 2: 86% vs. 72.7%; p = 0.05).

This study evaluated the supplementation of a precision biotic (PB) on the enterohepatic health markers and growth performance of broiler chickens undergoing an enteric challenge. In the first study, three treatments were used: Unchallenged Control (UC); Challenged Control (CC; dietary challenge and 10× dose of coccidia vaccine); and a challenged group supplemented with PB (1.3 kg/ton). In the second study, three treatments were used: control diet, diet supplemented with Avilamycin (10 ppm), and a diet supplemented with PB (0.9 kg/ton). All the birds were exposed to natural challenge composed by dietary formulation and reused litter from a coccidiosis positive flock. In Trial 1, PB decreased ileal histological damage, increased villi length, and the expression of SLC5A8 in ileal tissue versus CC; it reduced ileal expression of IL-1β compared to both UC and CC treatments. PB increased the expression of cell cycling gene markers CCNA2 and CDK2 in the ileum compared to CC. In Trial 2, PB improved the growth performance, intestinal lesion scores and intestinal morphology of broiler chickens. These results indicate that birds supplemented with PB are more resilient to enteric challenges, probably by its action in modulating microbiome metabolic pathways related to nitrogen metabolism and protein utilization.

Isolated distal deep–vein thrombosis (DVT, infra-popliteal DVT without pulmonary embolism) is a common presentation of venous thromboembolism (VTE), but was an exclusion criterion from the pivotal trials that validated the use of direct oral anticoagulants (DOACs) for VTE management. Using data from the international RIETE registry, we analyzed and compared trends in DOACs prescription between January 2011 and June 2019 in patients with distal vs. proximal DVT. We also assessed DOACs’ prescriptions and compared the outcomes (VTE recurrence, bleeding and death) of distal DVT patients treated with DOACs vs. those on vitamin K antagonists (VKAs). 2308 patients with distal DVT and 11,364 patients with proximal DVT were included in the current analysis. DOACs were more frequently prescribed in patients with distal than proximal DVT (25% vs. 16%, p < 0.001). DOACs use increased sharply during the observation period (P < 0.001 for trend). In 2018, 56% of patients with distal DVT received DOACs. Distal DVT patients treated with rivaroxaban or edoxaban received the dose recommended for VTE management in most (> 85%) cases. Patients treated with apixaban were older, more likely to have underlying conditions than patients treated with rivaroxaban and, in most cases (> 75%), did not receive the recommended 1-week loading dose for acute VTE management. Outcomes between distal DVT patients treated with VKAs or DOACs appeared to be similar. In patients with distal DVT, DOACs have become the most common anticoagulant regimen. Specific trials are needed to determine the optimal DOACs dose regimen for treatment of distal DVT.

The objective of this study was to evaluate the effects of the dietary supplementation of Bacillus subtilis DSM 32315 (probiotic) on the performance and intestinal microbiota of broiler chickens infected with Clostridium perfringens (CP). One-day-old broiler chickens were assigned to 3 treatments with 8 replicate pens (50 birds/pen). The treatments were: non-infected control; infected control; and infected supplemented with probiotic (1 × 106 CFU/g of feed). On day of hatch, all birds were sprayed with a coccidia vaccine based on the manufacturer recommended dosage. On d 18–20 the infected birds were inoculated with CP via feed. Necrotic enteritis (NE) lesion score was performed on d 21. Digestive tract of 2 birds/pen was collected on d 21 to analyze the ileal and cecal microbiota by 16S rRNA sequencing. Performance was evaluated on d 28 and 42. On d 21, probiotic supplementation reduced (p < 0.001) the severity of NE related lesion versus infected control birds. On d 28, feed efficiency was improved (p < 0.001) in birds supplemented with probiotic versus infected control birds. On d 42, body weight gain (BW gain) and feed conversion ratio (FCR) were improved (p < 0.001) in probiotic supplemented birds versus infected control birds. The diversity, composition and predictive function of the intestinal microbial digesta changed with the infection but the supplementation of probiotic reduced these variations. Therefore, dietary supplementation of Bacillus subtilis DSM 32315 was beneficial in attenuating the negative effects of CP challenge on the performance and intestinal microbiota of broilers chickens.

Venous thromboembolism (VTE) is a major cause of death in the world. After the acute-phase treatment, the optimal duration of anticoagulation is still debatable. The latest guidelines suggest maintaining long-term anticoagulation in patients with cancer-associated thrombosis (CAT) or with unprovoked VTE and a low bleeding risk. Methods: The MAC Project is an ongoing prospective-cohort, multi-center, observational study in Italy. The project aims to collect real-life clinical information in unselected patients given oral anticoagulants for VTE over a 5-year follow-up period. There were no exclusion criteria, except for life expectancy <6 months and refusal to sign the informed consent form or to attend the planned follow-up visit. All patients were followed-up prospectively with clinical controls scheduled at 3, 6, and 12 months after the index event, and then annually for up to 5 years. The primary efficacy and safety outcomes were symptomatic recurrent VTE and major bleeding. Results: We analyzed 450 consecutive patients treated with rivaroxaban and referred them to the MAC Project database for unprovoked or recurrent VTE. Of these, 267 (55%) were unprovoked VTE, and 377 (87%) were symptomatic. We followed up with the patients for a mean of 22 months (Q1 10.7; Q3 37.4 months). Recurrent VTE occurred in 12 patients on rivaroxaban treatment (IR 1.7 per 100 person-years). Males had more recurrence than women. During the follow-up period, we recorded 13 (2.9%) major bleeding, 12 (2.7%) clinically relevant non-major bleeding, 8 minor bleeding, and no fatal bleeding events. Overall, bleeding events occurred in 33 (7.3%) patients, most occurring within the first 2 years of treatment. In addition, we observed a statistically significant higher incidence of bleeding in patients with a baseline HAS-BLED score of 3 to 4 compared with those with a score of 0 to 2, with most events occurring during the first 3 months of treatment (RR 5.9). Discussion: Rivaroxaban appears to be safe and effective for the long-term treatment of patients with recurrent or unprovoked VTE. Our results match previously published data, and we are confident that the continuation of the follow-up for up to 5 years will confirm these outcomes.

The objective of this study was to determine the effects of protected sodium butyrate (SB), and protected sodium butyrate plus essential oils (carvacrol and ginger; SBEO) on the cecal microbiota of broilers challenged with Eimeria maxima and Clostridium perfringens . Birds were assigned to 4 treatments (8 replicates pens of 58 birds/pen): unchallenged control; challenged control; challenged and supplemented with SB; challenged and supplemented with SBEO. On d 13, challenged birds were orally inoculated with ~5,000 Eimeria maxima oocysts. On d 18–19, the same birds were exposed to Clostridium perfringens via drinking water (~8 log CFU/ml). Cecal excreta was collected at d 12, 18, 21, and 28 for microbiota analysis through 16s rRNA sequencing using Illumina MiSeq platform and analyzed using QIIME v. 1.9.1 The cecal microbiota was analyzed over time within each experimental group. The inclusion of SB alone or in combination with EO contributed to larger variations in the cecal microbiota over time than the unsupplemented treatments, as shown by the diversity indices. The community structure and abundance of the cecal microbiota were significantly different across ages, especially in the groups supplemented with SB and SBEO. As shown in the PCoA analysis, the supplementation of SB led to a more stable microbial community and lower between-sample variability over time. In the unchallenged control birds, Ruminococcus decreased ( p = 0.006), whereas Bacteroides and Clostridiales increased ( p ≤ 0.02) as the birds aged. In the challenged control group, however, the frequency of Coprococcus and Blautia decreased as birds aged ( p ≤ 0.01), and, Clostridiales did not increase. Supplementation of SB, but not SBEO, increased the frequency of Lactobacillus ( p = 0.01) on d 12 compared to d 18 and d 28, and prevented the reduction in the frequency of Blautia as the birds aged. Nevertheless, supplementation of SB and SBEO contributed to unique changes in the predicted functions of the cecal microbiota over time, which was not observed in the unsupplemented birds. SB and SBEO modulated the diversity, composition, and predictive function of the cecal microbiota which may have lowered the negative impact of necrotic enteritis (NE).

Extended-phase anticoagulation with direct oral Xa inhibitors (OAXI) is suggested in patients with cancer-associated venous thromboembolism (CAT). We report on patients enrolled in the MAC (Monitoring AntiCoagulants) Project, given rivaroxaban as extended-phase anticoagulation after CAT. The primary efficacy outcome was the incidence of symptomatic recurrent VTE; the primary safety outcomes were incidence of major and non-major clinically relevant bleeding, adverse events, and all-cause mortality. The mean patients’ follow-up was 19 months (SD 16); 64/604 (11%) had CAT. Recurrent VTE occurred in 9.3% and in 8.1% of patients with and without CAT (OR 1.2, 95% CI 0.5 to 2.9; p = 0.6). Major bleeding occurred in 4.7% and in 2.6%, respectively (OR = 1.8, 95% CI 0.5 to 6.6, p = 0.4), and non-major clinically-relevant bleeding in 4.7% and in 4.1% (OR = 1.2, 95% CI 0.3 to 3.9, p = 0.7). The relative figures for fatal haemorrhage and all-cause death were 1.6% versus 0%, and 1.6% versus 0.4%. Rivaroxaban appears to be effective and safe as extended-phase anticoagulation in patients with CAT. The mean treatment period was 3-times the standard 6-month course.